Impaired lung function and the development of cardiovascular disease

Impaired lung function is a prevalent condition in the general population, posing a significant risk for morbidity and mortality. There is a well-documented association between compromised lung function and increased susceptibility to cardiovascular disease (CVD). However, further research is needed to fully elucidate the underlying mechanisms and implications of this relationship. Notably, atherosclerosis, which is characterized by endothelial dysfunction in its early stages, underpins most CVD cases.

To expand our knowledge on endothelial dysfunction and lung function, Study I investigated three distinct measurements of endothelial function alongside three different measurements of lung function in two community-based cohorts. The results indicated a modest association between reduced endothelial-dependent vasodilation (EDV), as measured invasively, and forced expiratory volume in one second percent of predicted value (FEV1 %pred). This novel finding suggests that endothelial dysfunction in the pulmonary vasculature may play a role in the deterioration of lung function early in the disease process.

There are many biomarkers associated with CVD, but their relationship with impaired lung function remains less clear. Study II delve into specific protein biomarkers associated with CVD, seeking to determine their relevance in the context of diminished lung function. Three different study designs were utilized. Firstly, a cross-sectional analysis found that 22 out of 79 CVD protein biomarkers were associated with lower FEV1 %pred. Secondly, of these 22 proteins, only two proteins were linked to a more rapid decline of FEV1 %pred over a five-year period using a prospective cohort design in one of the study cohorts. Thirdly, causal inference was explored using Mendelian randomization in the UK Biobank, testing these two proteins. This analysis provided evidence supporting a potential causal role for growth-differentiation 15 (GDF-15) in the reduction of FEV1.

Study III involved an additional investigation of protein biomarkers and lung function, examining 242 proteins linked to CVD or metabolism and its association to FEV1 %pred, forced vital capacity (FVC) %pred, and FEV1/FVC ratio. The results indicated that five proteins were significantly associated with either higher or lower FEV1%pred. In contrast, nine proteins were associated with either higher or lower FVC %pred. Notably, no proteins showed associations with the FEV1/FVC ratio in either cohort. These results suggest that the protein biomarkers were mainly associated with lower lung volume rather than airway obstruction.

Study IV examined the impact of lower lung function and adverse outcomes in UK Biobank, a large-scale community database comprising approximately half a million participants. This study uncovered a progressive rise in both overall and cardiovascular mortality, myocardial infarction, ischemic stroke, and heart failure, with lower FEV1 or FVC %pred. This trend was consistent regardless of whether the individuals exhibited normal spirometry at the outset or not. Lastly, we compared the population attributable fraction (PAF) and reported that lower FEV1 %pred and FVC %pred were at least as influential as established risk factors like diabetes, chronic kidney disease, and hypertension in determining the risk of adverse outcomes.

The findings derived from these studies not only illuminate the pivotal role of lung function as a predictor of adverse outcomes but also emphasize its significance within the established landscape of CVD risk factors. Moreover, it underscores the importance of maintaining healthy blood vessels for overall health.

However, despite an extensive exploration of protein biomarkers associated with cardiovascular disease, no potential biomarker candidate suitable for clinical use for lung function was identified. This outcome raises the possibility that pursuing individual biomarkers in this context may not be the most viable path forward.

List of scientific papers

This thesis is based on the four following papers:

I. Endothelial dysfunction is associated with impaired lung function in two independent community cohorts. Rydell A, Janson C, Lisspers K, Ställberg B, Nowak C, Carlsson AC, Feldreich T, Iggman D, Lind L, Ärnlöv J. Respir Med. 2018 Oct;143:123-128.
https://doi.org/10.1016/j.rmed.2018.09.009

II. Plasma proteomics and lung function in four community-based cohorts. Rydell A, Nowak C, Janson C, Lisspers K, Ställberg B, Iggman D, Leppert J, Hedberg P, Sundström J, Ingelsson E, Lind L, Ärnlöv J. Respir Med. 2021 Jan;176:106282.
https://doi.org/10.1016/j.rmed.2020.106282

III. Cardiovascular disease-linked plasma proteins are mainly associated with lung volume. Rydell A*, Nerpin E*, Zhou X, Lind L, Lindberg E, Theorell Haglow J, Fall T, Janson C, Lisspers K, Elmståhl S, Zaigham S, Melander O, Nilsson PM, Ärnlöv J, Malinovschi A. ERJ Open Res. 2023 Mar 27;9(2):00321-2022.
https://doi.org/10.1183/23120541.00321-2022

IV. FEV1 and FVC as Robust Risk Factors for Cardiovascular Disease and Mortality: Insights from a Large Population Study. Rydell A, Janson C, Lisspers K, Yi-Ting Lin, Ärnlöv J. Respir Med. 2024 Jun;227:107614.
https://doi.org/10.1016/j.rmed.2024.107614

*Equal contribution